Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome, including glucose dysregulation, insulin insensitivity, and/or obesity, are linked to cognitive decline in aging. Moreover, the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD), selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists, improve several aspects of metabolic syndrome including lowering insulin resistance, glucose and cholesterol levels in Type 2 diabetics, and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However, the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood, and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years, we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently, our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here, we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs), NMDARs, Ca2+-induced Ca2+ release (CICR), and the Ca2+-dependent afterhyperpolarization (AHP), thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine, at 7-8 and 18-20 months of age, which component of metabolic dysregulation most closely associates with measures of cognitive function, and hippocampal electrophysiological/imaging function (L-VGCCs, NMDARs, CICR, AHPs, and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological, cognitive, gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices, testing for direct effects on electrophysiological markers of aging, and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together, these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore, even if the central hypothesis is rejected, the studies proposed will provide more definitive evidence for the impact o metabolic syndrome, as well as the actions of TZDs, on the brain. PUBLIC HEALTH RELEVANCE Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging, diabetes and obesity. If successful, our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.